GLP-1 Receptor Agonist Lixisenatide in Patients With Type 2 Diabetes for Glycemic Control and Safety Evaluation, on Top of Basal Insulin +/- Sulfonylurea (GETGOAL-L-ASIA)
Study Details
Study Description
Brief Summary
The purpose of this study is to evaluate the benefits and risks of lixisenatide (AVE0010), in comparison to placebo, as an add-on treatment to basal insulin with or without sulfonylurea, over a period of 24 weeks of treatment.
The primary objective is to assess the effects of lixisenatide, when added to basal insulin, on glycemic control in terms of glycosylated hemoglobin (HbA1c) reduction at Week 24.
The secondary objectives are to assess the effects of lixisenatide on body weight, 2-hour postprandial plasma glucose (PPG) after standardized meal challenge test, percentage of patients reaching HbA1c less than 7 percent (%), percentage of patients reaching HbA1c less than or equal to 6.5%, fasting plasma glucose (FPG), change in 7-point self-monitored plasma glucose (SMPG) profiles, change in daily basal insulin and total insulin doses; to evaluate safety, tolerability, pharmacokinetics (PK), and anti-lixisenatide antibody development.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 3 |
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Lixisenatide 2-step initiation regimen of lixisenatide: 10 microgram (mcg) once daily (QD) for 1 week, followed by 15 mcg QD for 1 week, then 20 mcg QD up to Week 24. |
Drug: Lixisenatide (AVE0010)
Self-administered by subcutaneous injections once daily within the hour preceding breakfast.
Device: Pen auto-injector
Other Names:
Drug: Sulfonylurea
Sulfonylurea if given, to be continued at a stable dose.
Drug: Basal Insulin
To be continued at a stable dose.
|
| Placebo Comparator: Placebo 2-step initiation regimen of volume matching placebo: 10 mcg QD for 1 week, followed by 15 mcg QD for 1 week, then 20 mcg QD up to Week 24. |
Drug: Placebo
Self-administered by subcutaneous injections once daily within the hour preceding breakfast.
Device: Pen auto-injector
Other Names:
Drug: Sulfonylurea
Sulfonylurea if given, to be continued at a stable dose.
Drug: Basal Insulin
To be continued at a stable dose.
|
Outcome Measures
Primary Outcome Measures
- Absolute Change From Baseline in Glycosylated Hemoglobin (HbA1c) at Week 24 [Baseline, Week 24]
Change was calculated by subtracting baseline value from Week 24 value. The on-treatment period for this efficacy variable is the time from the first dose of study drug up to 3 days after the last dose of study drug or up to the introduction of rescue therapy, whichever is the earliest. For a patient to be included in mITT population, both baseline and at least 1 post baseline assessment for at least 1 efficacy variable, were required.
Secondary Outcome Measures
- Change From Baseline in 2-hour Postprandial Plasma Glucose (PPG) at Week 24 [Baseline, Week 24]
The 2-hour PPG test measured blood glucose 2 hours after eating a standardized meal. Change was calculated by subtracting baseline value from Week 24 value. The on-treatment period for this efficacy variable is the time from the first dose of study drug up to the last dosing day of study drug or up to the introduction of rescue therapy, whichever is the earliest. For a patient to be included in mITT population, both baseline and at least 1 post baseline assessment for at least 1 efficacy variable, were required.
- Change From Baseline in Body Weight at Week 24 [Baseline, Week 24]
Change was calculated by subtracting baseline value from Week 24 value. The on-treatment period for this efficacy variable is the time from the first dose of study drug up to 3 days after the last dose of study drug or up to the introduction of rescue therapy, whichever is the earliest. For a patient to be included in mITT population, both baseline and at least 1 post baseline assessment for at least 1 efficacy variable, were required.
- Change From Baseline in Average 7-Point Self Monitored Plasma Glucose (SMPG) Profile at Week 24 [Baseline, Week 24]
Patients recorded a 7-point plasma glucose profile measured before and 2 hours after each meal and at bedtime once in a week and the average value for the 7-time points was calculated. The on-treatment period for this efficacy variable is the time from the first dose of study drug up to the last dosing day of study drug or up to the introduction of rescue therapy, whichever is the earliest. For a patient to be included in mITT population, both baseline and at least 1 post baseline assessment for at least 1 efficacy variable, were required.
- Change From Baseline in Fasting Plasma Glucose (FPG) at Week 24 [Baseline, Week 24]
Change was calculated by subtracting baseline value from Week 24 value. The on-treatment period for this efficacy variable is the time from the first dose of study drug up to 1 day after the last dose of study drug or up to the introduction of rescue therapy, whichever is the earliest. For a patient to be included in mITT population, both baseline and at least 1 post baseline assessment for at least 1 efficacy variable, were required.
- Change From Screening in Total Insulin Dose at Week 24 [Screening, Week 24]
Change was calculated by subtracting screening value from Week 24 value. The on-treatment period for this efficacy variable is the time from the first dose of study drug up to the last dosing day of study drug or up to the introduction of rescue therapy, whichever is the earliest. For a patient to be included in mITT population, both baseline and at least 1 post baseline assessment for at least 1 efficacy variable, were required.
- Percentage of Patients With Glycosylated Hemoglobin (HbA1c) Level Less Than 7% at Week 24 [Week 24]
The on-treatment period for this efficacy variable is the time from the first dose of study drug up to 3 days after the last dose of study drug or up to the introduction of rescue therapy, whichever is the earliest. For a patient to be included in mITT population, both baseline and at least 1 post baseline assessment for at least 1 efficacy variable, were required.
- Percentage of Patients With Glycosylated Hemoglobin (HbA1c) Level Less Than or Equal to 6.5% at Week 24 [Week 24]
The on-treatment period for this efficacy variable is the time from the first dose of study drug up to 3 days after the last dose of study drug or up to the introduction of rescue therapy, whichever is the earliest. For a patient to be included in mITT population, both baseline and at least 1 post baseline assessment for at least 1 efficacy variable, were required.
- Percentage of Patients Requiring Rescue Therapy During 24-Week Period [Baseline up to Week 24]
Routine fasting SMPG and central laboratory FPG (and HbA1c after week 12) values were used to determine the requirement of rescue medication. If fasting SMPG value exceeded the specified limit for 3 consecutive days, the central laboratory FPG (and HbA1c after week 12) were performed. Threshold values - from baseline to Week 8: fasting SMPG/FPG >270 milligram/deciliter (mg/dL) (15.0 mmol/L), from Week 8 to Week 12: fasting SMPG/FPG >240 mg/dL (13.3 mmol/L), and from Week 12 to Week 24: fasting SMPG/FPG >200 mg/dL (11.1 mmol/L) or HbA1c >8.5%. For a patient to be included in mITT population, both baseline and at least 1 post baseline assessment for at least 1 efficacy variable, were required.
Other Outcome Measures
- Change From Baseline in Glucose Excursion at Week 24 [Baseline, Week 24]
Glucose excursion = 2-hour PPG minus plasma glucose 30 minutes prior to the standardized meal test, before study drug administration. Change was calculated by subtracting baseline value from Week 24 value. The on-treatment period for this efficacy variable is the time from the first dose of study drug up to the last dosing day of the study drug or up to the introduction of rescue therapy, whichever is the earliest. For a patient to be included in mITT population, both baseline and at least 1 post baseline assessment for at least 1 efficacy variable, were required.
- Percentage of Patients With at Least 5% Weight Loss From Baseline at Week 24 [Baseline, Week 24]
The on-treatment period for this efficacy variable is the time from the first dose of study drug up to 3 days after the last dose of study drug or up to the introduction of rescue therapy, whichever is the earliest. For a patient to be included in mITT population, both baseline and at least 1 post baseline assessment for at least 1 efficacy variable, were required.
- Number of Patients With Symptomatic Hypoglycemia and Severe Symptomatic Hypoglycemia [First dose of study drug up to 3 days after the last dose administration]
Symptomatic hypoglycemia was an event with clinical symptoms that were considered to result from a hypoglycemic episode with an accompanying plasma glucose less than 60 mg/dL (3.3 mmol/L) or associated with prompt recovery after oral carbohydrate, intravenous glucose, or glucagon administration if no plasma glucose measurement was available. Severe symptomatic hypoglycemia was symptomatic hypoglycemia event in which the patient required the assistance of another person and was associated with either a plasma glucose less than 36 mg/dL (2.0 mmol/L) or prompt recovery after oral carbohydrate, intravenous glucose, or glucagon administration, if no plasma glucose measurement was available.
Eligibility Criteria
Criteria
Inclusion Criteria:
- Type 2 diabetes mellitus, diagnosed for at least 1 year at the time of the screening visit, insufficiently controlled with basal insulin with or without sulfonylurea
Exclusion Criteria:
-
HbA1c less than (<) 7 percent (%) or greater than (>) 10% at screening
-
At the time of screening age <legal age of majority
-
Pregnant or breastfeeding women or women of childbearing potential with no effective contraceptive method
-
Type 1 diabetes mellitus
-
Treatment with basal insulin for less than 3 months prior to screening or insulin regimen changed during the last 3 months prior to screening
-
Basal insulin dose at screening <10 units/day and/or during the last 2 months dose not stable (+/- 20%)
-
Sulfonylurea not at a stable (unchanged) dose for at least 3 months prior to screening
-
FPG at screening >250 milligram/deciliter (mg/dL) (>13.9 millimole/liter [mmol/L])
-
History of hypoglycemia unawareness
-
Weight change of more than 5 kilogram (kg) during the 3 months preceding the screening visit
-
History of unexplained pancreatitis, chronic pancreatitis, pancreatectomy, stomach/gastric surgery, inflammatory bowel disease
-
History of metabolic acidosis, including diabetic ketoacidosis within 1 year prior to screening
-
Hemoglobinopathy or hemolytic anemia, receipt of blood or plasma products within 3 months prior to the time of screening
-
Within the last 6 months prior to screening: history of myocardial infarction, stroke, or heart failure requiring hospitalization
-
Known history of drug or alcohol abuse within 6 months prior to the time of screening
-
Cardiovascular, hepatic, neurological, endocrine disease, active malignant tumor or other major systemic disease or patients with short life expectancy making implementation of the protocol or interpretation of the study results difficult, history or presence of clinically significant diabetic retinopathy, history or presence of macular edema likely to require laser treatment within the study period
-
Uncontrolled or inadequately controlled hypertension at the time of screening with a resting systolic blood pressure or diastolic blood pressure >180 millimeter of mercury (mmHg) or >95 mmHg, respectively
-
Laboratory findings at the time of screening: aspartate aminotransferase, alanine aminotransferase, or alkaline phosphatase: >2 times upper limit of the normal (ULN) laboratory range; amylase and/or lipase: >3 times ULN; total bilirubin: >1.5 times ULN (except in case of Gilbert's syndrome); hemoglobin <11 gram/deciliter and/or neutrophils <1500 per cubic millimeter (mm3) and/or platelets <100 000/mm3; positive test for Hepatitis B surface antigen and/or Hepatitis C antibody and positive serum pregnancy test in females of childbearing potential
-
Any clinically significant abnormality identified on physical examination, laboratory tests, electrocardiogram, or vital signs at the time of screening that, in the judgment of the investigator or any sub-investigator, precludes safe completion of the study or constrains efficacy assessment
-
Patients who are considered by the investigator as inappropriate for this study for any reason (for example, impossibility to meet specific protocol requirements, such as scheduled visits, being able to do self-injections, likelihood of requiring treatment during the screening phase and treatment phase with drugs not permitted by the clinical study protocol)
-
Patient was an investigator or any sub-investigator, pharmacist, study coordinator, other study staff or relative thereof directly involved in the conduct of the protocol
-
Use of other oral or injectable antidiabetic or hypoglycemic agents other than sulfonylurea or basal insulin (for example, metformin, alpha glucosidase inhibitor, thiazolidinedione, rimonabant, exenatide, dipeptidyl peptidase 4 inhibitors, fast acting insulin for 1 week or more etc.) within 3 months prior to the time of screening
-
Use of systemic glucocorticoids (excluding topical application or inhaled forms) for 1 week or more within 3 months prior to the time of screening
-
Use of any investigational drug within 3 months prior to screening
-
Participation in any previous study with lixisenatide
-
End-stage renal disease defined by a serum creatinine clearance of <15 milliliter/minute (mL/min) (calculated by the Cockcroft and Gault formula) and/or patients on dialysis
-
Clinically relevant history of gastrointestinal disease associated with prolonged nausea and vomiting, including, but not limited to gastroparesis and gastroesophageal reflux disease requiring medical treatment, within 6 months prior to the time of screening
-
Allergic reaction to any glucagon like peptide-1 (GLP-1) agonist in the past (for example, exenatide, liraglutide) or to metacresol
-
Additional exclusion criteria at the end of the run-in phase: informed consent withdrawal; lack of compliance during the single-blind placebo run-in phase (>2 injections missed); and patient with any adverse event which could have precludes the inclusion in the study, as assessed by the investigator
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Sanofi-Aventis Administrative Office | Tokyo | Japan | ||
| 2 | Sanofi-Aventis Administrative Office | Seoul | Korea, Republic of | ||
| 3 | Sanofi-Aventis Administrative Office | Makati City | Philippines | ||
| 4 | Sanofi-Aventis Administrative Office | Taipei | Taiwan |
Sponsors and Collaborators
- Sanofi
Investigators
- Study Director: Clinical Sciences & Operations, Sanofi
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- EFC10887
Study Results
Participant Flow
| Recruitment Details | The study was conducted at 57 centers in 4 countries between March 10, 2009 and June 23, 2010. |
|---|---|
| Pre-assignment Detail | A total of 437 patients were screened of which 126 (28.8%) were screen failures; main reason for screen failure was glycosylated hemoglobin (HbA1c) values being out of the defined protocol range (greater than or equal to 7% and less than or equal to 10%). A total of 311 patients were randomized. |
| Arm/Group Title | Placebo | Lixisenatide |
|---|---|---|
| Arm/Group Description | 2-step initiation regimen of volume matching placebo: 10 microgram (mcg) once daily (QD) subcutaneously for 1 week, followed by 15 mcg QD for 1 week, then 20 mcg QD up to Week 24. | 2-step initiation regimen of lixisenatide: 10 mcg QD subcutaneously for 1 week, followed by 15 mcg QD for 1 week, then 20 mcg QD up to Week 24. |
| Period Title: Overall Study | ||
| STARTED | 157 | 154 |
| Safety Population | 157 | 154 |
| Modified Intent-to-Treat(mITT)Population | 157 | 154 |
| COMPLETED | 144 | 133 |
| NOT COMPLETED | 13 | 21 |
Baseline Characteristics
| Arm/Group Title | Placebo | Lixisenatide | Total |
|---|---|---|---|
| Arm/Group Description | 2-step initiation regimen of volume matching placebo: 10 mcg QD subcutaneously for 1 week, followed by 15 mcg QD for 1 week, then 20 mcg QD up to Week 24. | 2-step initiation regimen of lixisenatide: 10 mcg QD subcutaneously for 1 week, followed by 15 mcg QD for 1 week, then 20 mcg QD up to Week 24. | Total of all reporting groups |
| Overall Participants | 157 | 154 | 311 |
| Age (years) [Mean (Standard Deviation) ] | |||
| Mean (Standard Deviation) [years] |
58.0
(10.1)
|
58.7
(10.2)
|
58.4
(10.2)
|
| Sex: Female, Male (Count of Participants) | |||
| Female |
77
49%
|
85
55.2%
|
162
52.1%
|
| Male |
80
51%
|
69
44.8%
|
149
47.9%
|
| Race/Ethnicity, Customized (participants) [Number] | |||
| Race: Asian/Oriental |
157
100%
|
154
100%
|
311
100%
|
| Ethnicity: Non Hispanic |
157
100%
|
154
100%
|
311
100%
|
| Glycosylated Hemoglobin (HbA1c) (percentage of hemoglobin) [Mean (Standard Deviation) ] | |||
| Mean (Standard Deviation) [percentage of hemoglobin] |
8.52
(0.78)
|
8.54
(0.73)
|
8.53
(0.76)
|
| Body Weight (kilogram (kg)) [Mean (Standard Deviation) ] | |||
| Mean (Standard Deviation) [kilogram (kg)] |
65.60
(12.47)
|
65.93
(13.00)
|
65.77
(12.72)
|
| 2-Hour Postprandial Plasma Glucose (PPG) (millimole per liter (mmol/L)) [Mean (Standard Deviation) ] | |||
| Mean (Standard Deviation) [millimole per liter (mmol/L)] |
17.75
(3.94)
|
17.81
(3.36)
|
17.78
(3.66)
|
| Number of Patients With Screening HbA1c Less Than 8% (participants) [Number] | |||
| Number [participants] |
36
22.9%
|
35
22.7%
|
71
22.8%
|
| Number of Patients With Screening HbA1c Greater Than or Equal to 8% (participants) [Number] | |||
| Number [participants] |
121
77.1%
|
119
77.3%
|
240
77.2%
|
| Fasting Plasma Glucose (FPG) (mmol/L) [Mean (Standard Deviation) ] | |||
| Mean (Standard Deviation) [mmol/L] |
7.75
(2.25)
|
7.67
(2.32)
|
7.71
(2.28)
|
| Average 7-point Self-Monitored Plasma Glucose (SMPG) (mmol/L) [Mean (Standard Deviation) ] | |||
| Mean (Standard Deviation) [mmol/L] |
11.42
(2.46)
|
11.58
(2.51)
|
11.51
(2.48)
|
| Glucose Excursion (mmol/L) [Mean (Standard Deviation) ] | |||
| Mean (Standard Deviation) [mmol/L] |
9.70
(4.19)
|
9.72
(3.27)
|
9.71
(3.75)
|
| Basal Insulin Treatment Duration (years) [Mean (Standard Deviation) ] | |||
| Mean (Standard Deviation) [years] |
3.01
(4.27)
|
2.94
(3.67)
|
2.97
(3.97)
|
| Total Insulin Dose (units per day) [Mean (Standard Deviation) ] | |||
| Mean (Standard Deviation) [units per day] |
24.11
(14.18)
|
24.85
(13.96)
|
24.48
(14.05)
|
| Number of Patients With Insulin Therapy at Screening (participants) [Number] | |||
| Glargine |
92
58.6%
|
95
61.7%
|
187
60.1%
|
| Detemir |
42
26.8%
|
41
26.6%
|
83
26.7%
|
| Neutral Protamine Hagedorn (NPH) |
21
13.4%
|
18
11.7%
|
39
12.5%
|
| Premix (Mixed Insulin) |
2
1.3%
|
0
0%
|
2
0.6%
|
| Duration of Diabetes (years) [Mean (Standard Deviation) ] | |||
| Mean (Standard Deviation) [years] |
14.13
(7.72)
|
13.71
(7.73)
|
13.92
(7.71)
|
| Sulfonylurea Treatment Duration (years) [Mean (Standard Deviation) ] | |||
| Mean (Standard Deviation) [years] |
6.80
(5.24)
|
5.33
(4.83)
|
6.07
(5.08)
|
| Number of Patients With Sulfonylurea Use (participants) [Number] | |||
| Yes |
111
70.7%
|
108
70.1%
|
219
70.4%
|
| No |
46
29.3%
|
46
29.9%
|
92
29.6%
|
| Body Mass Index (BMI) (kilogram per square meter (kg/m^2)) [Mean (Standard Deviation) ] | |||
| Mean (Standard Deviation) [kilogram per square meter (kg/m^2)] |
25.15
(3.94)
|
25.36
(3.69)
|
25.26
(3.82)
|
Outcome Measures
| Title | Absolute Change From Baseline in Glycosylated Hemoglobin (HbA1c) at Week 24 |
|---|---|
| Description | Change was calculated by subtracting baseline value from Week 24 value. The on-treatment period for this efficacy variable is the time from the first dose of study drug up to 3 days after the last dose of study drug or up to the introduction of rescue therapy, whichever is the earliest. For a patient to be included in mITT population, both baseline and at least 1 post baseline assessment for at least 1 efficacy variable, were required. |
| Time Frame | Baseline, Week 24 |
Outcome Measure Data
| Analysis Population Description |
|---|
| mITT population:all randomized patients who received at least 1 dose;had baseline,at least 1 post-baseline efficacy assessment, irrespective of compliance with study protocol/procedures. Last observation carried forward used. Number of patients analyzed=patients with baseline and at least 1 post-baseline HbA1c assessment during on treatment period. |
| Arm/Group Title | Placebo | Lixisenatide |
|---|---|---|
| Arm/Group Description | 2-step initiation regimen up to a maintenance dose of 20 mcg of volume matching placebo. | 2-step initiation regimen up to a maintenance dose of 20 mcg of lixisenatide. |
| Measure Participants | 154 | 146 |
| Least Squares Mean (Standard Error) [percentage of hemoglobin] |
0.11
(0.131)
|
-0.77
(0.137)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Placebo, Lixisenatide |
|---|---|---|
| Comments | To detect a difference of 0.5% in change from baseline to Week 24 in HbA1c between lixisenatide and placebo, 145 patients in each arm would provide a power of 90% assuming common standard deviation of 1.3% with a 2-sided t test at 5% significance level. | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | <0.0001 |
| Comments | Statistical testing: 2-sided at significance level=0.05. Analysis of co-variance(ANCOVA)included treatment arms, randomization strata of screening HbA1c (<8.0, >=8.0%),sulfonylurea use (yes, no), country as fixed effects, baseline HbA1c as covariate. | |
| Method | ANCOVA | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Least squares (LS) mean difference |
| Estimated Value | -0.88 | |
| Confidence Interval |
(2-Sided) 95% -1.116 to -0.650 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 0.118 |
|
| Estimation Comments | ||
| Title | Change From Baseline in 2-hour Postprandial Plasma Glucose (PPG) at Week 24 |
|---|---|
| Description | The 2-hour PPG test measured blood glucose 2 hours after eating a standardized meal. Change was calculated by subtracting baseline value from Week 24 value. The on-treatment period for this efficacy variable is the time from the first dose of study drug up to the last dosing day of study drug or up to the introduction of rescue therapy, whichever is the earliest. For a patient to be included in mITT population, both baseline and at least 1 post baseline assessment for at least 1 efficacy variable, were required. |
| Time Frame | Baseline, Week 24 |
Outcome Measure Data
| Analysis Population Description |
|---|
| mITT population. Missing data was imputed using last observation carried forward (LOCF). Here, number of patients analyzed = patients with baseline and at least 1 post-baseline 2-hour PPG assessment during on-treatment period. |
| Arm/Group Title | Placebo | Lixisenatide |
|---|---|---|
| Arm/Group Description | 2-step initiation regimen up to a maintenance dose of 20 mcg of volume matching placebo. | 2-step initiation regimen up to a maintenance dose of 20 mcg of lixisenatide. |
| Measure Participants | 142 | 131 |
| Least Squares Mean (Standard Error) [mmol/L] |
-0.14
(0.563)
|
-7.96
(0.598)
|
| Title | Change From Baseline in Body Weight at Week 24 |
|---|---|
| Description | Change was calculated by subtracting baseline value from Week 24 value. The on-treatment period for this efficacy variable is the time from the first dose of study drug up to 3 days after the last dose of study drug or up to the introduction of rescue therapy, whichever is the earliest. For a patient to be included in mITT population, both baseline and at least 1 post baseline assessment for at least 1 efficacy variable, were required. |
| Time Frame | Baseline, Week 24 |
Outcome Measure Data
| Analysis Population Description |
|---|
| mITT population. Missing data was imputed using LOCF. Here, number of patients analyzed = patients with baseline and at least 1 post-baseline body weight assessment during on-treatment period. |
| Arm/Group Title | Placebo | Lixisenatide |
|---|---|---|
| Arm/Group Description | 2-step initiation regimen up to a maintenance dose of 20 mcg of volume matching placebo. | 2-step initiation regimen up to a maintenance dose of 20 mcg of lixisenatide. |
| Measure Participants | 157 | 150 |
| Least Squares Mean (Standard Error) [kilogram] |
0.06
(0.271)
|
-0.38
(0.284)
|
| Title | Change From Baseline in Average 7-Point Self Monitored Plasma Glucose (SMPG) Profile at Week 24 |
|---|---|
| Description | Patients recorded a 7-point plasma glucose profile measured before and 2 hours after each meal and at bedtime once in a week and the average value for the 7-time points was calculated. The on-treatment period for this efficacy variable is the time from the first dose of study drug up to the last dosing day of study drug or up to the introduction of rescue therapy, whichever is the earliest. For a patient to be included in mITT population, both baseline and at least 1 post baseline assessment for at least 1 efficacy variable, were required. |
| Time Frame | Baseline, Week 24 |
Outcome Measure Data
| Analysis Population Description |
|---|
| mITT population. Missing data was imputed using LOCF. Here, number of patients analyzed = patients with baseline and at least 1 post-baseline average 7-point SMPG assessment during on-treatment period. |
| Arm/Group Title | Placebo | Lixisenatide |
|---|---|---|
| Arm/Group Description | 2-step initiation regimen up to a maintenance dose of 20 mcg of volume matching placebo. | 2-step initiation regimen up to a maintenance dose of 20 mcg of lixisenatide. |
| Measure Participants | 138 | 142 |
| Least Squares Mean (Standard Error) [mmol/L] |
-0.56
(0.271)
|
-1.91
(0.272)
|
| Title | Change From Baseline in Fasting Plasma Glucose (FPG) at Week 24 |
|---|---|
| Description | Change was calculated by subtracting baseline value from Week 24 value. The on-treatment period for this efficacy variable is the time from the first dose of study drug up to 1 day after the last dose of study drug or up to the introduction of rescue therapy, whichever is the earliest. For a patient to be included in mITT population, both baseline and at least 1 post baseline assessment for at least 1 efficacy variable, were required. |
| Time Frame | Baseline, Week 24 |
Outcome Measure Data
| Analysis Population Description |
|---|
| mITT population. Missing data was imputed using LOCF. Here, number of patients analyzed = patients with baseline and at least 1 post-baseline FPG assessment during on-treatment period. |
| Arm/Group Title | Placebo | Lixisenatide |
|---|---|---|
| Arm/Group Description | 2-step initiation regimen up to a maintenance dose of 20 mcg of volume matching placebo. | 2-step initiation regimen up to a maintenance dose of 20 mcg of lixisenatide. |
| Measure Participants | 157 | 148 |
| Least Squares Mean (Standard Error) [mmol/L] |
0.25
(0.302)
|
-0.42
(0.314)
|
| Title | Change From Screening in Total Insulin Dose at Week 24 |
|---|---|
| Description | Change was calculated by subtracting screening value from Week 24 value. The on-treatment period for this efficacy variable is the time from the first dose of study drug up to the last dosing day of study drug or up to the introduction of rescue therapy, whichever is the earliest. For a patient to be included in mITT population, both baseline and at least 1 post baseline assessment for at least 1 efficacy variable, were required. |
| Time Frame | Screening, Week 24 |
Outcome Measure Data
| Analysis Population Description |
|---|
| mITT population. Missing data was imputed using LOCF. Here, number of patients analyzed = patients with baseline and at least 1 post baseline insulin dose assessment during on-treatment period. |
| Arm/Group Title | Placebo | Lixisenatide |
|---|---|---|
| Arm/Group Description | 2-step initiation regimen up to a maintenance dose of 20 mcg of volume matching placebo. | 2-step initiation regimen up to a maintenance dose of 20 mcg of lixisenatide. |
| Measure Participants | 157 | 151 |
| Least Squares Mean (Standard Error) [units per day] |
-0.11
(0.442)
|
-1.39
(0.458)
|
| Title | Percentage of Patients With Glycosylated Hemoglobin (HbA1c) Level Less Than 7% at Week 24 |
|---|---|
| Description | The on-treatment period for this efficacy variable is the time from the first dose of study drug up to 3 days after the last dose of study drug or up to the introduction of rescue therapy, whichever is the earliest. For a patient to be included in mITT population, both baseline and at least 1 post baseline assessment for at least 1 efficacy variable, were required. |
| Time Frame | Week 24 |
Outcome Measure Data
| Analysis Population Description |
|---|
| mITT population. Missing data was imputed using LOCF. Here, number of patients analyzed = patients with baseline and at least 1 post-baseline HbA1c assessment during on-treatment period. |
| Arm/Group Title | Placebo | Lixisenatide |
|---|---|---|
| Arm/Group Description | 2-step initiation regimen up to a maintenance dose of 20 mcg of volume matching placebo. | 2-step initiation regimen up to a maintenance dose of 20 mcg of lixisenatide. |
| Measure Participants | 154 | 146 |
| Number [percentage of participants] |
5.2
3.3%
|
35.6
23.1%
|
| Title | Percentage of Patients With Glycosylated Hemoglobin (HbA1c) Level Less Than or Equal to 6.5% at Week 24 |
|---|---|
| Description | The on-treatment period for this efficacy variable is the time from the first dose of study drug up to 3 days after the last dose of study drug or up to the introduction of rescue therapy, whichever is the earliest. For a patient to be included in mITT population, both baseline and at least 1 post baseline assessment for at least 1 efficacy variable, were required. |
| Time Frame | Week 24 |
Outcome Measure Data
| Analysis Population Description |
|---|
| mITT population. Missing data was imputed using LOCF. Here, number of patients analyzed = patients with baseline and at least 1 post-baseline HbA1c assessment during on-treatment period. |
| Arm/Group Title | Placebo | Lixisenatide |
|---|---|---|
| Arm/Group Description | 2-step initiation regimen up to a maintenance dose of 20 mcg of volume matching placebo. | 2-step initiation regimen up to a maintenance dose of 20 mcg of lixisenatide. |
| Measure Participants | 154 | 146 |
| Number [percentage of participants] |
1.3
0.8%
|
17.8
11.6%
|
| Title | Change From Baseline in Glucose Excursion at Week 24 |
|---|---|
| Description | Glucose excursion = 2-hour PPG minus plasma glucose 30 minutes prior to the standardized meal test, before study drug administration. Change was calculated by subtracting baseline value from Week 24 value. The on-treatment period for this efficacy variable is the time from the first dose of study drug up to the last dosing day of the study drug or up to the introduction of rescue therapy, whichever is the earliest. For a patient to be included in mITT population, both baseline and at least 1 post baseline assessment for at least 1 efficacy variable, were required. |
| Time Frame | Baseline, Week 24 |
Outcome Measure Data
| Analysis Population Description |
|---|
| mITT population. Missing data was imputed using LOCF. Here, number of patients analyzed = patients with baseline and at least 1 post-baseline glucose excursion assessment during on-treatment period. |
| Arm/Group Title | Placebo | Lixisenatide |
|---|---|---|
| Arm/Group Description | 2-step initiation regimen up to a maintenance dose of 20 mcg of volume matching placebo. | 2-step initiation regimen up to a maintenance dose of 20 mcg of lixisenatide. |
| Measure Participants | 142 | 131 |
| Least Squares Mean (Standard Error) [mmol/L] |
0.14
(0.542)
|
-7.09
(0.576)
|
| Title | Percentage of Patients With at Least 5% Weight Loss From Baseline at Week 24 |
|---|---|
| Description | The on-treatment period for this efficacy variable is the time from the first dose of study drug up to 3 days after the last dose of study drug or up to the introduction of rescue therapy, whichever is the earliest. For a patient to be included in mITT population, both baseline and at least 1 post baseline assessment for at least 1 efficacy variable, were required. |
| Time Frame | Baseline, Week 24 |
Outcome Measure Data
| Analysis Population Description |
|---|
| mITT population. Missing data was imputed using LOCF. Here, number of patients analyzed = patients with baseline and at least 1 post-baseline body weight assessment during on-treatment period. |
| Arm/Group Title | Placebo | Lixisenatide |
|---|---|---|
| Arm/Group Description | 2-step initiation regimen up to a maintenance dose of 20 mcg of volume matching placebo. | 2-step initiation regimen up to a maintenance dose of 20 mcg of lixisenatide. |
| Measure Participants | 157 | 150 |
| Number [percentage of participants] |
4.5
2.9%
|
7.3
4.7%
|
| Title | Percentage of Patients Requiring Rescue Therapy During 24-Week Period |
|---|---|
| Description | Routine fasting SMPG and central laboratory FPG (and HbA1c after week 12) values were used to determine the requirement of rescue medication. If fasting SMPG value exceeded the specified limit for 3 consecutive days, the central laboratory FPG (and HbA1c after week 12) were performed. Threshold values - from baseline to Week 8: fasting SMPG/FPG >270 milligram/deciliter (mg/dL) (15.0 mmol/L), from Week 8 to Week 12: fasting SMPG/FPG >240 mg/dL (13.3 mmol/L), and from Week 12 to Week 24: fasting SMPG/FPG >200 mg/dL (11.1 mmol/L) or HbA1c >8.5%. For a patient to be included in mITT population, both baseline and at least 1 post baseline assessment for at least 1 efficacy variable, were required. |
| Time Frame | Baseline up to Week 24 |
Outcome Measure Data
| Analysis Population Description |
|---|
| mITT population. |
| Arm/Group Title | Placebo | Lixisenatide |
|---|---|---|
| Arm/Group Description | 2-step initiation regimen up to a maintenance dose of 20 mcg of volume matching placebo. | 2-step initiation regimen up to a maintenance dose of 20 mcg of lixisenatide. |
| Measure Participants | 157 | 154 |
| Number [percentage of participants] |
3.2
2%
|
1.3
0.8%
|
| Title | Number of Patients With Symptomatic Hypoglycemia and Severe Symptomatic Hypoglycemia |
|---|---|
| Description | Symptomatic hypoglycemia was an event with clinical symptoms that were considered to result from a hypoglycemic episode with an accompanying plasma glucose less than 60 mg/dL (3.3 mmol/L) or associated with prompt recovery after oral carbohydrate, intravenous glucose, or glucagon administration if no plasma glucose measurement was available. Severe symptomatic hypoglycemia was symptomatic hypoglycemia event in which the patient required the assistance of another person and was associated with either a plasma glucose less than 36 mg/dL (2.0 mmol/L) or prompt recovery after oral carbohydrate, intravenous glucose, or glucagon administration, if no plasma glucose measurement was available. |
| Time Frame | First dose of study drug up to 3 days after the last dose administration |
Outcome Measure Data
| Analysis Population Description |
|---|
| Safety population included all randomized patients who were exposed to at least 1 dose of study drug, regardless of the amount of treatment administered. |
| Arm/Group Title | Placebo | Lixisenatide |
|---|---|---|
| Arm/Group Description | 2-step initiation regimen up to a maintenance dose of 20 mcg of volume matching placebo. | 2-step initiation regimen up to a maintenance dose of 20 mcg of lixisenatide. |
| Measure Participants | 157 | 154 |
| Symptomatic hypoglycemia |
37
23.6%
|
66
42.9%
|
| Severe symptomatic hypoglycemia |
0
0%
|
0
0%
|
Adverse Events
| Time Frame | First dose of study drug up to 3 days after the last dose administration | |||
|---|---|---|---|---|
| Adverse Event Reporting Description | Median exposure to study treatment was 169 days in both arms. The analysis was performed on safety population, defined as all randomized patients who were exposed to at least 1 dose of study drug, regardless of the amount of treatment administered. | |||
| Arm/Group Title | Placebo | Lixisenatide | ||
| Arm/Group Description | 2-step initiation regimen up to a maintenance dose of 20 mcg of volume matching placebo. | 2-step initiation regimen up to a maintenance dose of 20 mcg of lixisenatide. | ||
All Cause Mortality |
||||
| Placebo | Lixisenatide | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | / (NaN) | / (NaN) | ||
Serious Adverse Events |
||||
| Placebo | Lixisenatide | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 9/157 (5.7%) | 10/154 (6.5%) | ||
| Eye disorders | ||||
| Hyphaema | 1/157 (0.6%) | 0/154 (0%) | ||
| Retinal haemorrhage | 1/157 (0.6%) | 0/154 (0%) | ||
| Gastrointestinal disorders | ||||
| Colonic polyp | 1/157 (0.6%) | 1/154 (0.6%) | ||
| Nausea | 0/157 (0%) | 1/154 (0.6%) | ||
| Vomiting | 0/157 (0%) | 1/154 (0.6%) | ||
| Hepatobiliary disorders | ||||
| Liver disorder | 1/157 (0.6%) | 0/154 (0%) | ||
| Infections and infestations | ||||
| Herpes zoster oticus | 0/157 (0%) | 1/154 (0.6%) | ||
| Pneumonia | 1/157 (0.6%) | 0/154 (0%) | ||
| Upper respiratory tract infection | 0/157 (0%) | 1/154 (0.6%) | ||
| Injury, poisoning and procedural complications | ||||
| Cartilage injury | 0/157 (0%) | 1/154 (0.6%) | ||
| Hand fracture | 0/157 (0%) | 1/154 (0.6%) | ||
| Joint injury | 0/157 (0%) | 1/154 (0.6%) | ||
| Lower limb fracture | 1/157 (0.6%) | 0/154 (0%) | ||
| Skin laceration | 1/157 (0.6%) | 0/154 (0%) | ||
| Neoplasms benign, malignant and unspecified (incl cysts and polyps) | ||||
| Breast cancer | 1/157 (0.6%) | 0/154 (0%) | ||
| Rectal cancer | 1/157 (0.6%) | 0/154 (0%) | ||
| Nervous system disorders | ||||
| Cerebral infarction | 0/157 (0%) | 2/154 (1.3%) | ||
| Psychiatric disorders | ||||
| Completed suicide | 1/157 (0.6%) | 0/154 (0%) | ||
| Reproductive system and breast disorders | ||||
| Uterine prolapse | 0/157 (0%) | 1/154 (0.6%) | ||
| Respiratory, thoracic and mediastinal disorders | ||||
| Asthma | 1/157 (0.6%) | 0/154 (0%) | ||
| Nasal septum deviation | 1/157 (0.6%) | 0/154 (0%) | ||
| Vascular disorders | ||||
| Hypertensive crisis | 0/157 (0%) | 1/154 (0.6%) | ||
Other (Not Including Serious) Adverse Events |
||||
| Placebo | Lixisenatide | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 71/157 (45.2%) | 125/154 (81.2%) | ||
| Gastrointestinal disorders | ||||
| Abdominal discomfort | 1/157 (0.6%) | 11/154 (7.1%) | ||
| Constipation | 4/157 (2.5%) | 8/154 (5.2%) | ||
| Diarrhoea | 4/157 (2.5%) | 10/154 (6.5%) | ||
| Dyspepsia | 0/157 (0%) | 11/154 (7.1%) | ||
| Nausea | 7/157 (4.5%) | 61/154 (39.6%) | ||
| Vomiting | 3/157 (1.9%) | 28/154 (18.2%) | ||
| General disorders | ||||
| Asthenia | 12/157 (7.6%) | 10/154 (6.5%) | ||
| Infections and infestations | ||||
| Nasopharyngitis | 20/157 (12.7%) | 21/154 (13.6%) | ||
| Metabolism and nutrition disorders | ||||
| Decreased appetite | 0/157 (0%) | 10/154 (6.5%) | ||
| Hypoglycaemia | 37/157 (23.6%) | 67/154 (43.5%) | ||
| Nervous system disorders | ||||
| Dizziness | 8/157 (5.1%) | 13/154 (8.4%) | ||
| Headache | 3/157 (1.9%) | 16/154 (10.4%) | ||
Limitations/Caveats
More Information
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
If no publication has occurred within 12 months of the completion of the study, the Investigator shall have the right to publish/present independently the results of the study. The Investigator shall provide the Sponsor with a copy of any such presentation/publication for comment at least 30 days before any presentation/submission for publication. If requested by the Sponsor, any presentation/submission shall be delayed up to 90 days, to allow the Sponsor to preserve its proprietary rights.
Results Point of Contact
| Name/Title | Trial Transparency Team |
|---|---|
| Organization | Sanofi |
| Phone | |
| Contact-us@sanofi.com |
- EFC10887